WO2017096042A1 - Compositions polymères sensibles au ph, kits et procédés - Google Patents

Compositions polymères sensibles au ph, kits et procédés Download PDF

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Publication number
WO2017096042A1
WO2017096042A1 PCT/US2016/064420 US2016064420W WO2017096042A1 WO 2017096042 A1 WO2017096042 A1 WO 2017096042A1 US 2016064420 W US2016064420 W US 2016064420W WO 2017096042 A1 WO2017096042 A1 WO 2017096042A1
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polymeric composition
composition
relaxation time
monomer
crosslinker
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PCT/US2016/064420
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English (en)
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Gregory James Ekchian
Michael J. Cima
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Massachusetts Institute Of Technology
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04—Acids; Metal salts or ammonium salts thereof
    • C08F220/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14539—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring pH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/04—Homopolymers or copolymers of esters
    • C08L33/14—Homopolymers or copolymers of esters of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/84—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving inorganic compounds or pH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2800/00—Copolymer characterised by the proportions of the comonomers expressed
    • C08F2800/20—Copolymer characterised by the proportions of the comonomers expressed as weight or mass percentages

Definitions

  • pH-sensitive hydrogels such as those that include poly- hydroxy ethylmethacrylate (p-HEMA) crosslinked with N,N'-methylenebisacrylamide (BIS), p- HEMA-BIS hydrogels have been used as sensors, because the transverse relaxation time (T 2 ) of the p-HEMA-BIS hydrogels can depend on the pH of the environments in which the hydrogels are disposed.
  • p-HEMA poly- hydroxy ethylmethacrylate
  • BIOS N,N'-methylenebisacrylamide
  • a single T 2 relaxation time can correspond to two, non-peak pH values, thereby imparting ambiguity to the results provided by the p-HEMA-BIS hydrogels.
  • a T 2 relaxation time of about 200 ms corresponds to the peak pH of about 6.5
  • a T 2 relaxation time of about 150 ms may correspond to an off-peak pH of about 6 and an off-peak pH of about 7.5.
  • the polymeric compositions may comprise a crosslinked co-polymer comprising a cationic monomer, an anionic monomer, and a crosslinker.
  • the mol ratio of the cationic monomer to the anionic monomer may be about 75:25 to about 25:75.
  • the cationic monomer may comprise a side chain having a tertiary amine, and the anionic monomer may comprise a side chain having a carboxylic acid.
  • the crosslinker may comprise at least one of a diacrylate crosslinker and a dimethacrylate crosslinker.
  • the methods may comprise associating a polymeric composition as provided herein with one or more biological tissues, one or more biological liquids, or a combination thereof, measuring a relaxation time of the polymeric composition, and determining a pH of the one or more biological tissues, one or more biological liquids, or a combination thereof by comparing the relaxation time of the polymeric composition with a standard curve comprising a plot and/or table of at least two known pH values and at least two previously measured relaxation times of the polymeric composition at the at least two known pH values.
  • Kits of parts also are provided, which may comprise a polymeric composition as provided herein, and a standard curve comprising a plot and/or table of at least two known pH values and at least two previously measured relaxation times of the polymeric composition at the at least two known pH values.
  • the methods may comprise providing a mixture comprising an anionic monomer, a cationic monomer, and a crosslinker, contacting the mixture with at least one initiator to form a polymerizable
  • the mol ratio of the cationic monomer to the anionic monomer in the mixture is about 75:25 to about 25:75.
  • the crosslinker may be present in the mixture at a concentration of about 0.01 to about 10 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker, or, alternatively, about 0.01 to about 10 mol %, based on the total amount of cationic and anionic monomer.
  • compositions comprising a first polymeric composition comprising a first crosslinked co-polymer comprising a first cationic monomer, a first anionic monomer, and a first crosslinker.
  • the first polymeric composition may have a relaxation time that is a function of pH, and the relaxation time may be unique at each pH within a range of about 4.5 to about 8.
  • the compositions may further include at least one of [1] a second polymeric composition and [2] at least one additional pH sensitive material.
  • the first polymeric composition, the second polymeric composition, and the at least one additional pH sensitive material may have maximum relaxation times that occur at different pH values, compared to one another.
  • FIG. 1 depicts plots of pH versus T 2 relaxation time for several embodiments of polymeric compositions having different ratios of monomers.
  • FIG. 2 depicts a plot of pH versus T 2 relaxation time for one embodiment of a polymeric composition within one possible range of pH values.
  • FIG. 3 depicts one embodiment of a two-compartment sensor and one embodiment of a mixture of particles that include a polymeric composition associated with a tissue.
  • pH-sensitive polymeric compositions may have a relaxation time that corresponds to a single pH value within certain detection ranges.
  • the relaxation time of the polymeric compositions provided herein is unique at each pH within a range of about 4.5 to about 8, about 5 to about 8, about 6 to about 8, about 5 to about 7.5, about 5.5 to about 7.5, about 6 to about 7.5, or about 6.5 to about 7.5.
  • the relaxation time of the polymeric compositions provided herein is the transverse relaxation time (T 2 ). In another embodiment, the relaxation time of the polymeric compositions provided herein is the longitudinal relaxation time (Ti).
  • the polymeric compositions provided herein comprise a crosslinked copolymer comprising a cationic monomer, an anionic monomer, and a crosslinker.
  • the mol ratio of the cationic monomer to the anionic monomer may be about 75:25 to about 25:75, about 70:30 to about 30:70, about 65:35 to about 35:65, about 65:35 to about 55:45, or about 60:40.
  • the mol ratio of the cationic monomer to the anionic monomer can be selected to ensure that each relaxation time of the polymeric compositions provided herein corresponds to a single pH within a preferred detection range of pH values.
  • the phrases "pH sensitive” and “pH sensitivities” generally refer to or describe polymeric compositions or other compositions having relaxation times that are affected by pH.
  • a change of pH may cause a corresponding change of a T 2 relaxation time and/or a Ti relaxation time of a polymeric composition or other composition, or, in other words, the T 2 relaxation time and/or T 1 relaxation time of the polymeric composition or other composition is a function of pH.
  • the cationic monomer of the polymeric compositions provided herein generally may be any monomer that is capable of forming a biocompatible polymer, and comprises a side chain that includes a moiety that can be positively charged at a certain pH or pH range.
  • Each cationic monomer may include identical side chains, or the cationic monomer may comprise a mixture of two or more monomers, each having a different side chain.
  • the cationic monomer comprises a side chain that includes a tertiary amine. In one embodiment, the cationic monomer comprises [1] a side chain that includes a tertiary amine, and [2] an acrylate moiety. In another embodiment, the cationic monomer comprises [1] a side chain that includes a tertiary amine, and [2] a methacrylate moiety.
  • the cationic monomer comprises a mixture of cationic monomers comprising a side chain that includes a tertiary amine, wherein a first portion of the cationic monomers includes a methacrylate moiety, and a second portion of the cationic monomers includes an acrylate moiety. Therefore, the cationic monomer can include a mixture of cationic monomers that include different side chains, and/or different polymerizable moieties, such as acrylate or methacrylate moieties.
  • the cationic monomer comprises a monomer of formula (I):
  • R 1 is selected from hydrogen or a monovalent Ci hydrocarbyl
  • R 2 is selected from a divalent Ci-C 6 hydrocarbyl
  • R 3 and R 4 are independently selected from a Ci-C 6 hydrocarbyl.
  • the monomers herein such as those of formula (I) are depicted in isolated form for clarity, it is understood by persons of skill in the art that the monomers have a different structure when polymerized and/or crosslinked to form the polymeric compositions provided herein.
  • a polymeric composition comprises a monomer of formula (I) in its polymeric backbone
  • the monomer of formula (I) may have the following structure:
  • Ci-C 6 hydrocarbyl generally refers to aliphatic or aryl groups containing 1 to 6, 1 to 4, 1 to 3, 2, or 1 carbon atoms, respectively.
  • Examples of aliphatic groups include, but are not limited to, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an alkadienyl group, a cyclic group, and the like, and includes all substituted, unsubstituted, branched, and linear analogs or derivatives thereof, in each instance having 1 to 6, 1 to 4, 1 to 3, 2, or 1 carbon atoms, etc.
  • Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, and pentyl.
  • Cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkyl moieties have linear and/or branched portions.
  • Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, and 3- hexenyl.
  • alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 3 -methyl- 1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, and 5-hexyny.
  • aryl moieties include phenyl and any heteroatom substituted derivative thereof, such as pyridinyl.
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with a chemical moiety or functional group such as alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O) H-alkyl- or -alkyl HC(O)alkyl), tertiary amine (such as alkylamino, arylamino, arylalkylamino), aryl, aryloxy, azo, carbamoyl (- HC(O)O- alkyl- or -OC(O) H-alkyl), carbamyl (e.g., CO H
  • a chemical moiety or functional group such
  • the cationic monomer comprises a monomer of formula (I), wherein R 1 is a monovalent unsubstituted Ci hydrocarbyl, and R 2 is a divalent unsubstituted C 1 -C4 hydrocarbyl. Therefore, in these embodiments, the cationic monomer is a monomer of formula (IA):
  • the cationic monomer comprises a monomer of formula (IA), wherein each of R 3 and R 4 , independently, is a monovalent unsubstituted Ci-C 3 hydrocarbyl. Therefore, in these embodiments, the cationic monomer is a monomer of formula (IB):
  • the cationic monomer comprises a monomer of formula (I), wherein R 1 is a monovalent unsubstituted Ci hydrocarbyl, R 2 is a divalent unsubstituted C 2 hydrocarbyl, and R 3 and R 4 are monovalent unsubstituted Ci hydrocarbyls. Therefore, the cationic monomer, in these embodiments, is 2-(dimethylamino)ethyl methacrylate, which is commonly referred to as dimethylaminoethyl methacrylate (DMAEMA): (DMAEMA).
  • DMAEMA dimethylaminoethyl methacrylate
  • the cationic monomer comprises a monomer of formula (I), wherein R 1 is hydrogen, and R 2 is a divalent unsubstituted C 1 -C 4 hydrocarbyl. Therefore, in these embodiments, the cationic monomer is a monomer of formula (IC):
  • the cationic monomer comprises a monomer of formula (IC), wherein each of R 3 and R 4 , independently, is a monovalent unsubstituted C 1 -C3 hydrocarbyl. Therefore, in these embodiments, the cationic monomer is a monomer of formula (ID):
  • the cationic monomer comprises a monomer of formula (I), wherein R 1 is hydrogen, R 2 is a divalent unsubstituted C 2 hydrocarbyl, R 3 and R 4 are monovalent unsubstituted Ci hydrocarbyls. Therefore, the cationic monomer, in these embodiments, is 2- (dimethylamino)ethyl acrylate, which is commonly referred to as dimethylaminoethyl acrylate (DMAEA):
  • DAEA dimethylaminoethyl acrylate
  • the anionic monomer of the polymeric compositions provided herein generally may be any monomer that is capable of forming a biocompatible polymer, and comprises a side chain that includes a moiety that can be negatively charged at a certain pH or pH range.
  • Each anionic monomer may include identical side chains, or the anionic monomer may comprise a mixture of two or more monomers, each having a different side chain.
  • the anionic monomer comprises a side chain that includes a carboxylic acid, which may form a carboxylate anion.
  • the anionic monomer comprises [1] a side chain that includes a carboxylic acid, and [2] an acrylate moiety.
  • the anionic monomer comprises [1] a side chain that includes a carboxylic acid, and [2] a methacrylate moiety.
  • the anionic monomer comprises a mixture of anionic monomers comprising a side chain that includes a carboxylic acid, wherein a first portion of the anionic monomers includes a methacrylate moiety, and a second portion of the anionic monomers includes an acrylate moiety. Therefore, the anionic monomer can include a mixture of anionic monomers that include different side chains, and/or different polymerizable moieties, such as acrylate or methacrylate moieties.
  • the anionic monomer comprises a monomer of formula (II):
  • R 5 is a divalent Ci-C 6 hydrocarbyl
  • R 6 is selected from hydrogen or a monovalent Ci hydrocarbyl
  • m is 0 or 1.
  • the anionic monomer is a monomer of formula (II), wherein m is 1, R 6 is a monovalent unsubstituted Ci hydrocarbyl, i.e. , methyl, and R 5 is a monovalent unsubstituted C 1 -C 3 hydrocarbyl, and the anionic monomer is a monomer of formula (IIA):
  • the anionic monomer is a monomer of formula (II), wherein m is 1, R 6 is hydrogen, and R 5 is a monovalent unsubstituted C 1 -C 3 hydrocarbyl, and the anionic monomer is a monomer of formula (IIB):
  • the anionic monomer is a monomer of formula (II), wherein m is 0, R 6 is hydrogen, and the anionic monomer is acrylic acid.
  • any crosslinker may be used herein that is capable of reacting with at least one moiety of the cationic monomer, at least one moiety of the anionic monomer, or a combination thereof.
  • the crosslinker may preserve the biocompatibility of the resulting crosslinked polymer.
  • the crosslinker comprises at least one acrylate moiety. In one embodiment, the crosslinker comprises two acrylate moieties. The crosslinker, therefore, may be a diacrylate crosslinker.
  • the crosslinker comprises at least one methacrylate moiety. In one embodiment, the crosslinker comprises two methacrylate moieties. The crosslinker, therefore, may be a dimethacrylate crosslinker.
  • the crosslinker comprises at least one methacrylate moiety and at least one acrylate moiety. In one embodiment, the crosslinker comprises one acrylate moiety and one methacrylate moiety.
  • the crosslinker is a diacrylate crosslinker having a structure according to formula (III):
  • R is a divalent Ci-C 6 hydrocarbyl.
  • the crosslinker has a structure according to formula (III), wherein R 7 is a divalent unsubstituted C 2 hydrocarbyl, and the dimethacrylate crosslinker is ethylene glycol dimethacrylate (EGDMA).
  • the crosslinker is a diacrylate crosslinker having a structure according to formula (IV):
  • R is a divalent Ci-C 6 hydrocarbyl.
  • the crosslinker is a diacrylate crosslinker having a structure according to formula (IV), wherein R 8 is a divalent unsubstituted C 2 hydrocarbyl, and the diacrylate crosslinker is ethylene glycol diacrylate.
  • the crosslinker may be present in the polymeric compositions provided herein in any amount sufficient to impart one or more desired characteristics to the polymeric compositions.
  • the crosslinker is present in the polymeric compositions provided herein in an amount of about 0.01 to about 10.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker. In one embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 0.01 to about 5.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker. In another embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 1.0 to about 5.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker.
  • the crosslinker is present in the polymeric compositions provided herein in an amount of about 2.0 to about 4.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker. In a still further embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 2.5 to about 3.5 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker. In a particular embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 3.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker.
  • the crosslinker is present in the polymeric compositions provided herein in an amount of about 0.01 to about 10.0 mol %, based on the total amount of the cationic and the anionic monomer. In one embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 0.01 to about 5.0 mol %, based on the total amount of the cationic and the anionic monomer. In another embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 1.0 to about 5.0 mol %, based on the total amount of the cationic and anionic monomer. In a further,
  • the crosslinker is present in the polymeric compositions provided herein in an amount of about 2.0 to about 4.0 mol %, based on the total amount of the cationic and anionic monomer. In a still further embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 2.0 to about 3.0 mol %, based on the total amount of the cationic and anionic monomer. In a particular embodiment, the crosslinker is present in the polymeric compositions provided herein in an amount of about 2.0 mol %, based on the total amount of the cationic and anionic monomer.
  • the polymeric compositions generally may be formed by contacting an anionic monomer, a cationic monomer, and a crosslinker with an initiator.
  • the components may be contacted in any order.
  • the cationic monomer, the anionic monomer, and the crosslinker are combined, and then contacted with an initiator.
  • Other processes are possible, however, including contacting the anionic monomer and the cationic monomer with an initiator prior to contacting the monomers with a crosslinker.
  • the methods comprise providing a mixture comprising an anionic monomer, a cationic monomer, and a crosslinker; contacting the mixture with at least one initiator to form a polymerizable composition; and curing the polymerizable composition to form the polymeric composition.
  • the mixture comprising the anionic monomer, the cationic monomer, and the crosslinker may be formed by contacting the anionic monomer, the cationic monomer, and the crosslinker in any order.
  • the mixture may further comprise a liquid, such as water.
  • the water may be deionized water.
  • the mol ratios of the components in the mixture may be selected to facilitate the formation of the polymeric compositions provided herein.
  • the mol ratio of the cationic monomer to the anionic monomer in the mixture may be about 75:25 to about 25:75, about 70:30 to about 30:70, about 55:45 to about 65:35, or about 60:40.
  • the crosslinker may be present in the mixture at a concentration of about 0.01 to about 10 % by weight, about 1.0 to about 5.0 % by weight, about 2.0 to about 4.0 % by weight, about 2.5 to about 3.5 % by weight, or about 3.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker, or, alternatively, the crosslinker may be present in the mixture at a concentration of about 0.01 to about 10 mol %, about 1.0 to about 5.0 mol %, about 2.0 to about 4.0 mol %, about 2.0 to about 3.0 mol %, or about 2.0 mol %, based on the total amount of the cationic monomer and the anionic monomer.
  • the mol ratio of the cationic monomer to the anionic monomer in the mixture may be about 75:25 to about 25:75, and the crosslinker is present in the mixture at a concentration of about 0.01 to about 5 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker, or, alternatively, at a concentration of about 0.01 to about 5 mol %, based on the total amount of the cationic and anionic monomer.
  • the mol ratio of the cationic monomer to the anionic monomer in the mixture may be about 55:45 to about 65:35, and the crosslinker is present in the mixture at a concentration of about 2.0 to about 4.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker, or, alternatively about 2.0 to about 4.0 mol %, based on the total amount of the cationic and anionic monomer.
  • the mol ratio of the cationic monomer to the anionic monomer in the mixture may be about 60:40, and the crosslinker is present in the mixture at a concentration of about 3.0 % by weight, based on the total weight of the anionic monomer, the cationic monomer, and the crosslinker, or, alternatively, about 2.0 mol %, based on the total amount of the cationic and anionic monomer.
  • the mixture may be placed under vacuum.
  • the mixture may be kept under vacuum for about 1 to about 20 minutes, or longer.
  • the strength of the vacuum may be about 1 to about 6 torr.
  • the mixture is kept under a vacuum of about 3.5 torr for about 15 minutes.
  • thermal treatments include [1] a "room temperature (RT) treatment” in which the mixture is maintained at room temperature prior to initiator addition, [2] an “ice treatment” in which the mixture is placed in an ice bath for about 1 to about 20 minutes prior to initiator addition, and [3] a “chilling treatment” in which the mixtures is maintained at 4 °C for about 15 to about 45 minutes prior to initiator addition.
  • RT room temperature
  • ice treatment in which the mixture is placed in an ice bath for about 1 to about 20 minutes prior to initiator addition
  • a “chilling treatment” in which the mixtures is maintained at 4 °C for about 15 to about 45 minutes prior to initiator addition.
  • an initiator may be added to the mixture to form a polymerizable
  • the initiator may consist of one type of initiator, or the initiator may comprise two or more types of initiators. Generally, the initiator may include one or more compounds capable of facilitating the reaction of one or more of the components in the mixture.
  • the initiator comprises ammonium persulfate
  • the initiator consists of ammonium persulfate. In a further embodiment, the initiator consists of
  • the initiator consists of ammonium persulfate and tetramethylethylenediamine.
  • the initiator may be added to a liquid prior to its addition to the mixture.
  • the initiator is added to the mixture as an initiator solution.
  • the initiator solution may have an initiator concentration of about 0.5 mM to about 10 M.
  • the initiator solution may be added dropwise to the mixture.
  • the initiator comprises an initiator solution comprising ammonium persulfate, tetramethylethylenediamine, or a combination thereof. In another embodiment, the initiator is an initiator solution comprising ammonium persulfate. In a further embodiment, the initiator includes [1] an initiator solution comprising ammonium persulfate, and [2] neat tetramethy lethy 1 enedi amine .
  • the initiator may be added to the mixture in an amount effective to impart a desired concentration of the initiator in the mixture.
  • the initiator may be an initiator solution comprising ammonium persulfate, and the initiator solution may be added to mixture in an amount effective to impart the mixture with a concentration of ammonium persulfate of about 0.5 mM to about 6 mM, about 1 mM to about 5 mM, about 1 mM, or about 5 mM.
  • the initiator may be or include a neat initiator, and the neat initiator may be added to the mixture in an amount effective to impart the mixture with a concentration of the neat initiator, such as tetramethylethylenediamine, of about 0.5 mM to about 6 mM, about 1 mM to about 5 mM, about 1 mM, or about 5 mM.
  • a concentration of the neat initiator such as tetramethylethylenediamine
  • the at least one initiator comprises tetramethylethylenediamine and a liquid comprising ammonium persulfate, and, after contacting the mixture with the at least one initiator, the concentration of tetramethylethylenediamine in the mixture is about 5 mM, and the concentration of ammonium persulfate in the mixture is about 5 mM; and the polymeric composition has a transverse relaxation time of about 2500 ms to about 2800 ms at a pH of about 7.1 when the transverse relaxation time is measured at a field strength of about 0.5 T.
  • the at least one initiator comprises tetramethylethylenediamine and a liquid comprising ammonium persulfate, and, after contacting the mixture with the at least one initiator, the concentration of tetramethylethylenediamine in the mixture is about 5 mM, and the concentration of ammonium persulfate in the mixture is about 5 mM; and the polymeric composition has a transverse relaxation time of about 2400 ms to about 2700 ms at a pH of about 6.7 when the transverse relaxation time is measured at a field strength of about 0.5 T.
  • the at least one initiator comprises tetramethylethylenediamine and a liquid comprising ammonium persulfate, and, after contacting the mixture with the at least one initiator, the concentration of tetramethylethylenediamine in the mixture is about 1 mM, and the concentration of ammonium persulfate in the mixture is about 1 mM, and the polymeric composition is made by a process that includes the room temperature thermal treatment.
  • At least a portion of the components of the resulting polymerizable composition may polymerize, crosslink, or a combination thereof.
  • the polymerizable composition may be cured.
  • cured generally refer to a process that forms a desired polymeric composition by facilitating a desired degree of polymerization and/or crosslinking among the components of a polymerizable composition.
  • the polymerizable composition is cured at a temperature of about 60 °C to about 120 °C.
  • the curing process may last about 10 to about 45 minutes.
  • the polymerizable composition is cured at about 80 °C for about 30 minutes.
  • the polymerizable composition may be cured in a curing vessel capable of imparting a desired shape to the resulting polymeric composition.
  • the polymeric composition also may be sized and/or shaped, for example, by cutting or punching, after curing to impart the polymeric composition with a desired size and/or shape, regardless of the shape of the curing vessel.
  • the methods of pH sensing comprise providing a polymeric composition as provided herein; associating the polymeric composition with one or more biological tissues, one or more biological liquids, or a combination thereof; measuring a relaxation time of the polymeric composition; and determining a pH of the one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the associating step includes contacting the polymeric composition with the biological tissue or biological liquid in order to determine the pH of the biological liquid or tissue at, or about, the area of contact.
  • the one or more biological tissues, one or more biological liquids, or a combination thereof may be in vivo or in vitro.
  • associating the polymeric composition with the one or more biological tissues, the one or more biological liquids, or a combination thereof comprises disposing the polymeric composition [1] on at least one surface of the one or more biological tissues, the one or more biological liquids, or a combination thereof, [2] in the one or more biological tissues, the one or more biological liquids, or a combination thereof, or [3] a combination thereof.
  • a polymeric composition may be disposed on one or more surfaces of a tissue, and/or a polymeric composition may be injected into a tissue.
  • associating the polymeric composition with the one or more biological tissues, the one or more biological liquids, or a combination thereof comprises injecting the polymeric composition into the one or more biological tissues, the one or more biological liquids, or a combination thereof.
  • embodiments of the polymeric compositions provided herein are hydrogels that can be injectable and/or spreadable, and/or can avoid migration upon being associated with one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the polymeric compositions Before or after associating the polymeric compositions with one or more biological tissues, one or more biological liquids, or a combination thereof, the polymeric compositions may be allowed adequate time to cure or gel.
  • cure or “gel,” as those terms are used herein, it means that the one or more functional groups of the anionic monomer, cationic monomer, and/or crosslinker have undergone one or more reactions with each other to a degree sufficient to impart the polymeric composition with one or more desirable characteristics.
  • the relaxation time of the polymeric compositions may be determined by any means known in the art.
  • the T 1 relaxation time is determined with a magnetic resonance imaging scanner or bench top nuclear magnetic resonance (MR) system, and an inversion recovery pulse sequence.
  • the T 2 relaxation time is determined with a magnetic resonance imaging scanner or bench top NMR system, and a Car-Purcell- Meiboom-Gill (CPMG) pulse sequence.
  • the relaxation time of the polymeric compositions may be determined in vivo or in vitro.
  • a polymeric composition may be associated with one or more in vivo biological tissues, one or more in vivo biological liquids, or a combination thereof, and the polymeric composition may be analyzed by NMR while associated, or after being associated, with the one or more biological fluids, one or more biological liquids, or a combination thereof.
  • a sample of a polymeric composition associated with one or more in vivo biological tissues, one or more in vivo biological liquids, or a combination thereof may be collected and then analyzed by NMR. The collected sample may include at least a portion of the one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the relaxation time When the relaxation time is determined, it may be compared to a pre-determined standard curve to determine the pH of the one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the pre-determined standard curve may be established by plotting a series of known pH values versus the relaxation times of a polymeric composition at the known pH values.
  • each relaxation time determined for embodiments of the polymeric compositions corresponds to a single physiologically relevant pH, for example, a pH of 4 to 8.5, 4.5 to 8.5, 5.0 to 8.0, 5.5 to 8.0, 5.5 to 7.5, 6.0 to 7.5, or 6.0 to 7.0.
  • two or more polymeric compositions may be associated with one or more biological tissues, one or more biological liquids, or a combination thereof, in order to achieve a desired sensitivity within all or part of a particular pH range.
  • the two or more polymeric compositions may be combined with each other before and/or during their association with one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the two or more polymeric compositions may be associated with the one or more biological tissues, one or more biological liquids, or a combination thereof in a separate manner.
  • the two or more polymeric compositions may be disposed on and/or in a two compartment sensor with one compartment housing a first polymeric composition and the second compartment housing a second polymeric composition.
  • a first polymeric composition may be associated with one portion of a biological tissue
  • a second polymeric composition may be associated with a second portion of the biological tissue.
  • compositions other than the polymeric compositions provided herein may have different pH sensitivities
  • one or more of the polymeric compositions provided herein and at least one additional pH sensitive material may be associated with one or more biological tissues, one or more biological liquids, or a combination thereof, in order to achieve a desired sensitivity within all or part of a particular pH range.
  • the one or more polymeric compositions and the at least one additional pH sensitive material may be combined with each other before and/or during their association with one or more biological tissues, one or more biological liquids, or a combination thereof.
  • the one or more polymeric compositions and the at least one additional pH sensitive material may be associated with the one or more biological tissues, one or more biological liquids, or a combination thereof in a separate manner.
  • the one or more polymeric compositions and at least one additional pH sensitive material may be disposed on and/or in a two compartment sensor with one compartment housing a first polymeric composition and the second compartment housing at least one additional pH sensitive material.
  • FIG. 3 depicts one embodiment of two compartment sensor 30 that includes a first compartment 40 that houses a first polymeric composition, and a second compartment 50 that houses at least one additional pH sensitive material.
  • the two compartment sensor 30 is associated with a tissue 10, which may be tumor tissue.
  • a first polymeric composition may be associated with one portion of a biological tissue
  • at least one additional pH sensitive material may be associated with a second portion of the biological tissue.
  • the employment of one or more polymeric compositions and at least one additional pH sensitive material can permit the analysis of biological tissues, biological liquids, or a combination thereof that are spatially separated and/or mixed together.
  • the at least one additional pH sensitive material include p-HEMA and p-HEMA-BIS.
  • compositions are provided herein that comprise a first polymeric composition, as provided herein, and at least one of [1] a second polymeric composition, as provided herein, and [2] at least one additional pH sensitive material. Therefore, the compositions may include a first polymeric composition, as provided herein, and a second polymeric composition, as provided herein; or a first polymeric composition, as provided herein, and at least one additional pH sensitive material; or a first polymeric composition, as provided herein, a second polymeric composition, as provided herein, and at least one additional pH sensitive material.
  • the first polymeric composition, the second polymeric composition, and the at least one additional pH sensitive material have maximum relaxation times that occur at different pH values.
  • the first polymeric composition comprises a first crosslinked copolymer comprising a first cationic monomer, a first anionic monomer, and a first crosslinker; and the first polymeric composition has a relaxation time that is a function of pH; and the second polymeric composition comprises a second crosslinked co-polymer comprising a second cationic monomer, a second anionic monomer, and a second crosslinker, and the second crosslinked copolymer has a relaxation time that is a function of pH.
  • the relaxation time of the first polymeric composition may be unique at each pH within a range of about 4.5 to about 8, about 5 to about 8, about 6 to about 8, about 5 to about 7.5, about 5.5 to about 7.5, about 6 to about 7.5, or about 6.5 to about 7.5
  • the relaxation time of the second polymeric composition may be unique at each pH within a range of about 4.5 to about 8, about 5 to about 8, about 6 to about 8, about 5 to about 7.5, about 5.5 to about 7.5, about 6 to about 7.5, or about 6.5 to about 7.5.
  • the first polymeric composition, the second polymeric composition, and the at least one additional pH sensitive material may be in a particulate form, and the compositions may comprise a mixture of particles.
  • the mixture of particles may be measured in a single voxel, and the relaxation times of the first polymeric composition, the second polymeric composition, and the at least one additional pH sensitive material may be determined with a multi-exponential fitting.
  • FIG. 3 depicts a mixture of particles 20 comprising a first polymeric composition and at least one additional pH sensitive material that is associated with a tissue 10, which may be tumor tissue.
  • the polymeric compositions provided herein may be associated with any internal or external biological tissues and/or liquids, including human or other mammalian tissues and/or liquids.
  • the biological tissues and/or liquids may be natural or artificially generated, healthy or diseased, such as tumor tissue, or any combination thereof.
  • the biological liquids may be intracellular liquids, extracellular liquids, or any combination thereof.
  • the biological tissues and/or liquids may be in vivo or in vitro.
  • the biological tissues may be skin, bone, ocular, muscular, vascular, an internal organ, such as lung, intestine, heart, liver, etc., or any tumor, and the biological liquids may be blood, bile, lymph fluid, urine, any liquid affiliated with the foregoing biological tissues, or a combination thereof.
  • the one or more biological tissues comprises tumor tissue.
  • the tumor tissue may include the surface of the tumor, the intratumoral tissue, or a combination thereof.
  • the methods of pH sensing provided herein may be used as, or as part of, a medical treatment, including cancer treatment.
  • the pH sensing methods provided herein may be used to analyze metastasis, drug resistance, radiotherapy resistance, and/or therapeutic efficiency of cancer treatment.
  • the pH of intratumoral tissue typically decreases if the tumor is receptive to therapy and/or if the therapy has treated the tumor successfully ⁇ see, e.g., Lindner, D. et al. "Intra-tumoural extra-cellular pH: a useful parameter of response to chemotherapy in syngeneic tumour lines, " British Journal of Cancer (2009) 100, 21287-1291). Therefore, the pH sensing methods provided herein may be used to assess therapeutic efficiency, drug resistance, etc. by determining the pH of the intratumoral tissue.
  • the pH sensing methods also may be used to assist the selection of more aggressive cell phenotypes.
  • a kit in another aspect, comprises a polymeric composition and a standard curve.
  • the standard curve may depict a plot of pH versus the relaxation times of the polymeric composition.
  • the standard curve may be included as part of a sheet of instructions, or printed or embossed on any packaging associated with a kit.
  • kits comprise a vial, syringe, or other receptacle that includes the polymeric composition.
  • the kit comprises two or more vials, each containing a component of the polymeric composition.
  • the two or more vials may be the barrels of a double-barreled syringe.
  • the kit may further include an applicator or other device means, such as a syringe, for storing and/or delivering, via injection and/or topical application, the polymeric composition to one or more biological tissues, one or more biological liquids, or a combination thereof.
  • a polymeric composition was prepared by combining DMAEMA (1.501 g), acrylic acid (AA)(0.461 g), EGDMA (0.063 g), and deionized (DI) water (5.882 g) in a flask, and placing the contents of the flask under vacuum (3.5 torr) for 15 minutes.
  • APS ammonium persulfate
  • TEMED tetramethylethylenediamine
  • the prepolymer solution included the monomers (DMAEMA and acrylic acid), the crosslinker (EGDMA), DI water, and the initiators (APS and TEMED).
  • the curing vessel was then placed in an oven at 80 °C for 30 minutes.
  • the prepolymer solution was cured into a desired shape, which was imparted by the curing vessel.
  • One sample was cured into a disk-shaped product. Samples of the cured product also were cut into a desired shape, and punched into a desired shape.
  • Example 2 Preparation of Polymeric Compositions Having Different Ratios of Monomers Using the procedure of Example 1, four polymeric compositions were made having different mol ratios of monomers. The four polymeric compositions had mol ratios of
  • DMAEMA to acrylic acid of 75:25; 70:30; 60:40; and 25:75.
  • the T 2 relaxation times of the four polymeric compositions were measured with a bench top MR system ( MR minispec, Bruker, USA) and a Car-Purcell-Meiboom-Gill (CPMG) pulse sequence.
  • the temperature was 40 °C
  • B 0 0.5 T.
  • the plots of pH versus the T 2 relaxation times of the four polymeric compositions are depicted at FIG. 1.
  • the T 2 relaxation times of FIG. 2 generally followed as upward trend as the pH increased, especially within the pH range of 6 to 8.
  • a series of polymeric compositions having a 60:40 mol ratio of DMAEMA to acrylic acid was made with varying [1] types or combinations of initiators, [2] concentrations of initiator(s), and [3] thermal treatments prior to initiator addition.
  • RT room temperature
  • ice treatment in which the contents of the flask were placed in an ice bath for about 10 minutes prior to initiator addition
  • a "chilling treatment” in which the contents of the flask were maintained at 4 °C for 30 minutes prior to initiator addition.
  • Each polymeric composition of Table 1 was made in an 8 mL batch, and 1 mL of each of the polymeric compositions was placed, prior to curing, into six empty NMR tubes having a diameter of about 10 mm.

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Abstract

La présente invention concerne des compositions polymères présentant un temps de relaxation qui est une fonction du pH. Les compositions polymères peuvent comprendre un monomère anionique, un monomère cationique et un agent de réticulation. L'agent de réticulation peut comprendre au moins l'un parmi un agent de réticulation à fonction diacrylate et un agent de réticulation à fonction diméthacrylate. L'invention concerne également des procédés de détection de pH et des procédés de formation d'une composition polymère. Des kits de pièces qui comprennent une composition polymère sont également décrits. Les compositions polymères peuvent être utilisées pour déterminer le pH d'un ou plusieurs tissus et/ou de liquides biologiques.
PCT/US2016/064420 2015-12-01 2016-12-01 Compositions polymères sensibles au ph, kits et procédés WO2017096042A1 (fr)

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